Overexpression of erbB family members is a common feature of many human malignancies. P185 , EGFR, erbB3 and erbB4 receptors have been found to be abnormally distributed on a variety of human tumors and lead to the assembly of activating receptor complexes that cause and maintain the transformed state. These cell surface receptors represent therapeutic targets to control or reverse cancer growth. ErbB family members have an unusual relationship with another class of receptors, namely the TNF receptor system, in that they appear to regulate each other. The PI and others have begun to define this relationship biochemical. The goal of this set of studies is two-fold. 1) to extend our understanding of this complex relationship and 2) based on this information to develop small molecule peptidic antagonists to the members of the erbB receptor family and in particular to HER2 receptors. The PI will simultaneously create agonist mimetics that activate members of the TNF family of receptors. The intent is to treat tumors using small molecules so that within the ensemble of receptors on the surface, the erbB members responsible for transformation will be disabled and the sensitivity of the TNF family of receptors to novel ligands which promote cell death will be increased. The current proposal will provide knowledge and strategies for developing small molecules in receptor based therapies of pl85 receptor related cancers. The hypothesis underlying these aims is that small peptidomimetics may be more efficacious than macromolecules at in vivo anti-tumor biological activities.